The overall goal of this proposal is elucidation of key driving forces for evolution and mutagenesis of retroviruses. The hypothesis which is set forth is as follows: the dNTP substrate binding affinity of retroviral DNA polymerases, reverse transcriptases (RT), is a key determinant for 1) evolution rate and 2) cell type specificity of retroviruses. The fidelity ifference between RTs of two major groups of retroviruses, lentiviruses and onco-retroviruses is responsible for their mutatgenesis and evolution rate differences: In addition, onco-retroviruses exclusively infect dividing cells containing high cellular dNTP concentration, whereas lentiviruses uniquely infect non-dividing cells containing low dNTP concentrations as well as dividing cells. Therefore, the hypothesis is that dNTP binding affinity of RT is a determinant of cell type specificity of these two groups of retroviruses. This hypothesis will be tested using RTs from two retroviruses feline immunodeficiency virus (FIV) and feline leukemia virus (FeLV), which are isolated from a single host species.